The brain is unique in allowing only select access to molecules. While this is a useful protective mechanism, it also prevents potentially beneficial molecular agents from gaining access to the central nervous system (CNS), and as such, the molecular agents are unable to exert a therapeutic effect in many neurological disorders or other conditions of the CNS.
The blood-brain barrier (BBB) performs a neuroprotective function by tightly controlling access to the brain; consequently it also impedes access of pharmacological agents to cerebral tissues, necessitating the use of vectors for their transit. Blood-brain barrier (BBB) permeability is frequently a rate-limiting factor for the penetration of drugs or peptides into the CNS [Pardridge, Neurovirol. 5: 556-569 (1999); Bickel et al., Adv. Drug Deliv. Rev. 46: 247-279 (2001)]. The brain is shielded against potentially toxic substances by the BBB, which is formed by brain capillary endothelial cells that are closely sealed by tight junctions. In addition, brain capillaries possess few fenestrae and few endocytic vesicles, compared to the capillaries of other organs [Pardridge, Neurovirol. 5: 556-569 (1999)]. There is little transit across the BBB of large, hydrophilic molecules aside from some specific proteins such as transferrin, lactoferrin and low-density lipoproteins, which are taken up by receptor-mediated transcytosis (RMT) [Pardridge, Neurovirol. 5: 556-569 (1999); Tsuji et al., Adv. Drug Deliv. Rev. 36: 277-290 (1999); Kusuhara et al., Drug Discov. Today 6: 150-156 (2001); Dehouck et al. J. Cell. Biol. 138: 877-889 (1997); and Fillebeen et al., J. Biol. Chem. 274: 7011-7017 (1999)].
Malignant glioma (MG) represent the most prevalent and lethal primary cancer of the central nervous system. Patients diagnosed with the highest grade MG, grade IV glioblastoma multiforme (GBM), survive for only 9-12 months after diagnosis despite surgical resection and aggressive treatment regimens. Multimodal approaches using radiation with conjunctive chemotherapy (temozolamide (TMZ)) resulted in only marginal increase in patients' survival up to 14.6 months. Furthermore, recurrence is nearly universal and salvage therapies for such progression remain ineffective. GBM remains a highly enigmatic and incurable disease particularly due to a highly therapy-resistant cancer stem cell population (brain tumor stem cell, BTSC) and an incomplete understanding of how catalogued genetic aberrations dictate phenotypic hallmarks of the disease. It is highly resistant even to intense therapy (apoptosis) despite florid intratumoral necrogenesis. The continued lack of success in treating high-grade gliomas with targeted receptor tyrosine kinase inhibitors, which have been proven to be effective in other malignancies, has prompted a reevaluation of all aspects of glioma drug development and underlined the overarching need to develop an innovative technological platform and refine cell culture-based and in vivo model systems to combat the disease.